Physiochemical effects of acid exposure on bone composition and function.

Bone is primarily composed of collagen and apatite, two materials which exhibit a high sensitivity to pH dysregulation. As a result, acid exposure of bone, both clinically and in the laboratory is expected to cause compositional and mechanical changes to the tissue. Clinically, Metabolic acidosis (MA), a condition characterized by a reduced physiological pH, has been shown to have negative implications on bone health, including a decrease in bone mineral density and volume as well as increased fracture risk. The addition of bone-like apatite to ionic solutions such as phosphate buffered saline (PBS) and media has been shown to acidify the solution leading to bone acid exposure. Therefore, is it essential to understand how reduced pH physiochemically affects bone composition and in turn its mechanical properties. This study investigates the specific changes in bone due to physiochemical dissolution in acid. Excised murine bones were placed in PBS solutions at different pHs: a homeostatic pH level (pH 7.4), an acidosis equivalent (pH 7.0), and an extreme acidic solution (pH 5.5). After 5 days, the bones were removed from the solutions and characterized to determine compositional and material changes. We found that bones, without cells, were able to regulate pH via buffering, leading to a decrease in bone mineral content and an increase in collagen denaturation. Both of these compositional changes contributed to an increase in bone toughness by creating a more ductile bone surface and preventing crack propagation. Therefore, we conclude that the skeletal systems' physiochemical response to acid exposure includes multifaceted and spatially variable compositional changes that affect bone mechanics.

Acidosis induces significant changes to the murine supraspinatus enthesis organic matrix.

Rotator cuff pathology is a common musculoskeletal condition that disproportionately affects older adults, as well as patients with diabetes mellitus and chronic kidney disease. It is known that increased age and kidney dysfunction have been correlated to acidotic states, which may be related to the increased incidence of rotator cuff injury. In order to investigate the potential relationship between acidosis and rotator cuff composition and mechanics, this study utilizes a 14-day murine model of metabolic acidosis and examines the effects on the supraspinatus tendon-humeral head attachment complex. The elastic matrix in the enthesis exhibited significant changes beginning at day 3 of acidosis exposure. At day 3 and day 7 timepoints, there was a decrease in collagen content seen in both mineralized and unmineralized tissue as well as a decrease in mineral:matrix ratio. There is also evidence of both mineral dissolution and reprecipitation as buffering ions continually promote pH homeostasis. Mechanical properties of the tendon-to-bone attachment were studied; however, no significant changes were elicited in this 14-day model of acidosis. These findings suggest that acidosis can result in significant changes in enthesis composition over the course of 14 days; however, enthesis mechanics may be more structurally mediated rather than affected by compositional changes.

Is There a Community Microbial Community? A Comparison of Pathogens Between Two Hospital Surgical Intensive Care Units in a Single City.

Background: Nosocomial and health-care-associated infections drive increased healthcare costs and negatively affect patient outcomes. The human microbiome has been heavily explored in recent years with incomplete data regarding hospital-specific and community-specific microbial communities. Although bacterial species differ between intensive care units in the same hospital, it is unclear if they differ between similar units in similar hospitals in the same community. Our hypothesis is that pathogens in surgical intensive care units (SICUs) are distinct between hospitals, even in the same community. Methods: From 2017 to 2021, data were collected prospectively from the SICUs of two 400-bed hospitals located three miles apart in the same city (Hospital A and Hospital B). Infections defined using U.S. Centers for Disease Control and Prevention (CDC) criteria were recorded for trauma and general surgery patients, as well as patient demographics, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and causative organism. Results: Overall, Escherichia coli was the most commonly isolated pathogen in Hospital A, whereas Staphylococcus aureus was most commonly isolated at Hospital B. Enterococci were more common in Hospital A, and Haemophilus influenzae and Enterobacter spp. were more common in Hospital B. After stratification between trauma and non-trauma patients, however, these differences disappeared, with the exception of more overall gram-positive organisms and fewer gram-negative organisms among Hospital A trauma patients compared to Hospital B. There were no differences in rates of isolation of either fungi or resistant bacteria between hospitals. Conclusions: At a species level, admission diagnosis appears to be a greater determinant of pathogen isolation than hospital when comparing similar intensive care units (ICUs) in the same geographic area, but a larger body of data is needed to flesh out a distinct microbial map of the organisms occupying a certain geographic region. Further areas for investigation include comparison between hospital units, specific anatomic sites, and ICU versus floor patients.

Administration of alendronate exacerbates ammonium chloride-induced acidosis in mice.

Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic acid-induced bone dissolution. Bisphosphonates (BPPs) are a potential treatment for inhibiting bone dissolution; however, there are limited studies observing the use of BPPs on acidotic patients. We aimed to determine efficacy of BPPs on maintaining bone health and pH regulation in acid-exposed mice. Using a diet-induced murine model of metabolic acidosis, we examined bone structure, composition, and mechanics as well as blood gases for three groups: control, acidosis, and acidosis + bisphosphonates (acidosis+BPP). Acidosis was induced for 14 days and alendronate was administered every 3 days for the acidosis+BPP group. The administration of BPP had little to no effect on bone structure, mechanics, and composition of the acidosis bones. However, administration of BPP did cause the mice to develop more severe acidosis than the acidosis only group. Overall, we discovered that BPPs may exacerbate acidosis symptoms by inhibiting the release of buffering ions from bone. Therefore, we propose that BPP administration should be carefully considered for those with CKD and that alkali supplementation could help minimize acidifying effects.

Metabolic Acidosis Results in Sexually Dimorphic Response in the Heart Tissue.

Metabolic acidosis (MA) is a highly prevalent disorder in a significant proportion of the population, resulting from imbalance in blood pH homeostasis. The heart, being an organ with very low regenerative capacity and high metabolic activity, is vulnerable to chronic, although low-grade, MA. To systematically characterize the effect of low-grade MA on the heart, we treated male and female mice with NH4Cl supplementation for 2 weeks and analyzed their blood chemistry and transcriptomic signature of the heart tissue. The reduction of pH and plasma bicarbonate levels without an associated change in anion gap indicated a physiological manifestation of low-grade MA with minimal respiratory compensation. On transcriptomic analysis, we observed changes in cardiac-specific genes with significant gender-based differences due to MA. We found many genes contributing to dilated cardiomyopathy to be altered in males, more than in females, while cardiac contractility and Na/K/ATPase-Src signaling were affected in the opposite way. Our model presents a systems-level understanding of how the cardiovascular tissue is affected by MA. As low-grade MA is a common ailment with many dietary and pharmaceutical interventions, our work presents avenues to limit chronic cardiac damage and disease manifestation, as well as highlighting the sex differences in MA-induced cardiovascular damage.

Infection or Inflammation: Are Uncomplicated Acute Appendicitis, Acute Cholecystitis, and Acute Diverticulitis Infectious Diseases?

Background: It is recognized increasingly that common surgical infections of the peritoneal cavity may be treated with antibiotic agents alone, or source control surgery with short-course antimicrobial therapy. By extension, testable hypotheses have emerged that such infections may not actually be infectious diseases, but rather represent inflammation that can be treated successfully with neither surgery nor antibiotic agents. The aim of this review is to examine extant data to determine which of uncomplicated acute appendicitis (uAA), uncomplicated acute calculous cholecystitis (uACC), or uncomplicated mild acute diverticulitis (umAD) might be amenable to management using supportive therapy alone, consistent with the principles of antimicrobial stewardship. Methods: Review of pertinent English-language literature and expert opinion. Results: Only two small trials have examined whether uAA can be managed with observation and supportive therapy alone, one of which is underpowered and was stopped prematurely because of challenging patient recruitment. Data are insufficient to determine the safety and efficacy of non-antibiotic therapy of uAA. Uncomplicated acute calculous cholecystitis is not primarily an infectious disease; infection is a secondary phenomenon. Even when bactibilia is present, there is no high-quality evidence to suggest that mild disease should be treated with antibiotic agents. There is evidence to indicate that antibiotic prophylaxis is indicated for urgent/emergency cholecystectomy for uACC, but not in the post-operative period. Uncomplicated mild acute diverticulitis, generally Hinchey 1a or 1b in current nomenclature, does not benefit from antimicrobial agents based on multiple clinical studies. The implication is that umAD is inflammatory and not an infectious disease. Non-antimicrobial management is reasonable. Conclusions: Among the considered disease entities, the evidence is strongest that umAD is not an infectious disease and can be treated without antibiotic agents, intermediate regarding uACC, and lacking for uAA. A plausible hypothesis is that these inflammatory conditions are related to disruption of the normal microbiome, resulting in dysbiosis, which is defined as an imbalance of the natural microflora, especially of the gut, that is believed to contribute to a range of conditions of ill health. As for restorative pre- or probiotic therapy to reconstitute the microbiome, no recommendation can be made in terms of treatment, but it is not recommended for prevention of primary or recurrent disease.

Effects of acidosis on the structure, composition, and function of adult murine femurs.

Physiologic pH is maintained in a narrow range through multiple systemic buffering systems. Metabolic Acidosis (MA) is an acid-base disorder clinically characterized by a decrease in systemic pH and bicarbonate (HCO3-) levels. Acidosis affects millions annually, resulting in decreased bone mineral density and bone volume and an increased rate of fracture. We developed an adult murine model of diet-induced metabolic acidosis via graded NH4Cl administration that successfully decreased systemic pH over a 14 day period to elucidate the effects of acidosis on the skeletal system. Blood gas analyses measured an increase in blood calcium and sodium levels indicating a skeletal response to 14 days of acidosis. MA also significantly decreased femur ultimate strength, likely due to modifications in bone morphology as determined from decreased microcomputed tomography values of centroid distance and area moment of inertia. These structural changes may be caused by aberrant remodeling based on histological data evidencing altered OCL activity in acidosis. Additionally, we found that acidosis significantly decreased bone CO3 content in a site-specific manner similar to the bone phenotype observed in human MA. We determined that MA decreased bone strength thus increasing fracture risk, which is likely caused by alterations in bone shape and compounded by changes in bone composition. Additionally, we suggest the temporal regulation of cell-mediated remodeling in MA is more complex than current literature suggests. We conclude that our model reliably induces MA and has deleterious effects on skeletal form and function, presenting similarly to the MA bone phenotype in humans.